ALK1 receptor and ligand antagonists and uses thereof
Inventors
Grinberg, Asya • Knopf, John • Pearsall, Robert S. • Kumar, Ravindra • Seehra, Jasbir
Assignees
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Publication Number
US-12144860-B2
Publication Date
2024-11-19
Expiration Date
Abstract
In certain aspects, the present disclosure relates to the insight that a polypeptide comprising a ligand-binding portion of the extracellular domain of activin-like kinase I (ALK1) polypeptide may be used to inhibit angiogenesis in vivo, particularly in mammals suffering angiogenesis-related disorders. The disclosure also identifies ligands for ALK1 and demonstrates that such ligands have pro-angiogenic activity, and antibodies that inhibit receptor-ligand interaction.
Core Innovation
The disclosure characterizes activin-like kinase I (ALK1, ACVRL1) as an in vivo pro-angiogenic receptor for the GDF5-group ligands (GDF5/6/7) and the BMP9-group ligands (BMP9/10), and positions ALK1 as a therapeutic axis for anti-angiogenic intervention. Angiogenesis is described as being driven through ALK1 ligand signaling, including in VEGF-independent contexts.
The disclosure proposes ALK1-axis antagonists as anti-angiogenic therapies by providing agents that inhibit ALK1 ligand-receptor interactions and neutralize ALK1 ligand signaling. Identified agents include soluble ALK1 extracellular domain (ECD) polypeptides, including ALK1-Fc fusion proteins such as SEQ ID NO:3 and nucleic acids encoding ALK1-Fc (SEQ ID NO:4). These ALK1 ECD polypeptides are described as intended to inhibit angiogenesis and are associated with local (ocular) or systemic delivery.
The disclosure also identifies high-affinity ALK1-binding ligands within the GDF5/7/BMP9 group, with GDF6 and BMP10 referenced, and describes functional neutralization approaches using anti-ALK1 antibodies and antibodies targeting ALK1 ligands. DAN is described as a selective inhibitor that binds GDF5/6/7 but not BMP9/10, supporting bone/joint-selective angiogenesis inhibition. Documented findings include suppression of BMP9/SMAD signaling and anti-angiogenic effects in multiple in vivo contexts.
Claims Coverage
The partial claims provided identify two independent claims, each directed to an ALK1 fusion protein defined by the amino acid sequence of SEQ ID NO:3. Across the independent claims, the coverage centers on the defined ALK1 fusion protein sequence, with dependent claims further adding pharmaceutical preparation context and specifying a dimeric form.
ALK1 fusion protein defined by SEQ ID NO: 3
An activin-like kinase I (ALK1) fusion protein comprising the amino acid sequence of SEQ ID NO: 3.
ALK1 fusion protein consisting of SEQ ID NO: 3
An activin-like kinase I (ALK1) fusion protein consisting of the amino acid sequence of SEQ ID NO: 3.
Both independent claims are directed to an ALK1 fusion protein defined by SEQ ID NO: 3, with dependents specifying inclusion in a pharmaceutical preparation and, in some dependent claims, requiring the fusion protein to be present in a dimeric form.
Stated Advantages
Inhibits angiogenesis, including in VEGF-independent contexts, via ALK1-axis antagonists.
Provides ocular benefits.
Provides rheumatoid arthritis benefits.
Provides multiple myeloma benefits.
Neutralizes ALK1 ligand signaling, including suppression of BMP9/SMAD signaling as described in the disclosure.
Reduces ocular angiogenesis as reported in the disclosure.
Reduces lytic bone lesions and bone loss as reported in the disclosure.
Documented Applications
Anti-angiogenic therapy associated with ocular effects, including reduced ocular angiogenesis as reported.
Therapeutic application in murine rheumatoid arthritis, including collagen-induced arthritis model effects as reported.
Therapeutic application in multiple myeloma using the 5T2MM model, including reported reductions in lytic bone lesions and bone loss.
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